NO AND OXIDATIVE STRESS IN HUMAN MYOCARDIAL FAILURE

本项目的总体目标是确定心力衰竭（CHF）患者心肌一氧化氮（NO）和氧化应激的功能意义。最近的证据表明，NO在衰竭的人类心肌中增加，并且可能有助于CHF的病理生理学。 此外，在心力衰竭中已证实心肌氧化应激增加。 体外研究表明，活性氧（ROS）可对心肌产生直接毒性作用，与心肌收缩力受损、胎儿基因表达和细胞死亡相关。 此外，在动物模型中，抗氧化剂已被证明可以减弱ROS的负性肌力作用并防止心力衰竭的发展。在左心室（LV）衰竭中，心率介导的收缩力增加（力-频率关系）减弱、平稳甚至倒置。虽然心动过速无法增加收缩力可能导致CHF患者心输出量反应降低和运动不耐受，但其潜在机制尚不清楚。在具体目标1中，我们将通过测量冠状动脉内输注NG-单甲基-L-精氨酸（一种NOS抑制剂）之前和期间随心率增加而发生的LV压力上升峰值速率（+dP/dt）的变化，检验心肌NO合酶（NOS）活性增加减弱LV衰竭患者力-频率关系的假设。在具体目标2中，我们将通过确定冠状动脉内输注抗氧化剂抗坏血酸之前和期间的力-频率关系，检验心肌氧化应激增加减弱LV衰竭患者力-频率关系的假设。目的1和2是有创性的协议，将评估心肌NO和氧化应激在心力衰竭中的急性功能意义。在特定目标3中，我们将测试一种新型无创系统在扩张型心肌病患者心房起搏心动过速和冠状动脉内多巴酚丁胺输注期间通过测量LV收缩末期弹性来检测收缩状态急性变化的能力。如果我们证明这项新技术能够在导管室中测量收缩力的变化，我们将通过测量收缩性心力衰竭患者在抗氧化剂和/或抗炎剂治疗前后的收缩末期弹性来评估其检测LV性能慢性变化的能力。

The overall goal of this project is to determine the functional significance of myocardial nitric oxide (NO) and oxidative stress in humans with heart failure (CHF). Recent evidence suggests that NO is increased in failing human myocardium and may contribute to the pathophysiology of CHF. In addition, increased myocardial oxidative stress has been demonstrated in heart failure. In vitro studies indicate that reactive oxygen species (ROS) can exert direct toxic effects on the myocardium associated with impaired contractility, fetal gene expression and cell death. Moreover, antioxidants have been shown to attenuate the negative inotropic effects of ROS and prevent the development of heart failure in animal models. In left ventricular (LV) failure, the heart rate- mediated increase in contractility (force-frequency relationship) is attenuated, flat or even inverted. While the failure to increase contractility with tachycardia likely contributes to the reduced cardiac output response and exercise intolerance observed in patients with CHF, the underlying mechanisms are poorly understood. In Specific Aim 1, we will test the hypothesis that increased myocardial NO synthase (NOS) activity attenuates the force- frequency relationship in humans with LV failure by measuring the changes in the peak rate of rise of LV pressure (+dP/dt) that occur with increasing heart rates before and during intracoronary infusion of NG-monomethyl-L-arginine, an inhibitor of NOS. In Specific Aim 2, we will test the hypothesis that increased myocardial oxidative stress attenuates the force-frequency relationship in humans with LV failure by determining the force- frequency relationship before and during intracoronary infusion of the antioxidant ascorbic acid. Aims 1 and 2 are invasive protocols that will assess the acute functional significance of myocardial NO and oxidative stress in heart failure. In Specific Aim 3, we will test the ability of a novel, non-invasive system to detect acute changes in contractile state by measuring LV end-systolic elastance during atrial pacing tachycardia and intracoronary dobutamine infusion in patients with dilated cardiomyopathy. If we show that this new technology is able to measure changes in contractility in the catheterization laboratory, we will assess its ability to detect chronic changes in LV performance by measuring end-systolic elastance before and after therapy with antioxidants and/or anti- inflammatory agents in patients with systolic heart failure.